Members of the tumor necrosis factor (TNF) superfamily of cytokines influence a variety of immunological functions, including cellular activation, proliferation, and death, upon interaction with a corresponding superfamily of receptors (1-3). Interest in the apoptosis-inducing molecules TNF and Fas ligand has been peaked due to their participation in events such as autoimmune disorders, activation-induced cell death, immune privilege, and tumor evasion from the immune system (4-8). Another death-inducing family member, TRAIL(TNF-related apoptosis-inducing ligand, also referred to as Apo-2 ligand or Apo-2L) is generating excitement because of its apparent unique ability to induce apoptosis in a wide range of transformed cell lines but not in normal tissues and cells (9,10).
To date, four homologous, but distinct, human TRAIL receptors have been identified, with two [DR4(11; hereafter referred to as TRAIL-R1) and DR5/TRAIL-R2 (12-15)] having the ability to initiate the apoptosis signaling cascade after ligation and two [TRID/DcR1/TRAIL-R3 (12,13,15,16) and TRAIL-R4/DcR2/TRUNDD (17-19)] lacking this ability. Because they lack the ability to directly signal cell death, TRAIL-R3 and TRAIL-R4 have been hypothesized as being protective receptors, either by acting as “decoy” receptors (11,12,18,19) or via transduction of an anti-apoptotic signal (17).
Given the tumor cell-selectivity of TRAIL's cytotoxicity from results obtained in vitro, recent studies have examined the safety and antitumor activity of recombinant, soluble TRAIL in vivo (20-22). TRAIL was found to be well tolerated when multiple doses were given to normal animals, and no histological or functional changes were observed in any of the tissues or organs examined. These results were hemorrhage, and ultimately death (20,23,24). Moreover, multiple injections of soluble TRAIL into mice beginning the day after tumor implantation significantly suppressed the growth of the tumors, with many animals being tumor-free (20-22).
A major drawback to these findings was that large amounts of soluble TRAIL were required to inhibit tumor formation. This may be due to the pharmacokinetic profile of soluble TRAIL that indicated that after intravenous injection the majority of the protein is cleared within 5 hours (20). Increasing the in vivo half-life of recombinant soluble TRAIL or developing an alternative means of delivery may increase the relative tumoricidal activity of TRAIL such that larger, more establish tumors could be eradicated as efficiently as smaller tumors. The identification of alternate methods to deliver TRAIL to the tumor site, however, is also critical for the further development and testing of the antitumor activity of TRAIL in vivo.
The development of alternate or adjuvant forms of cancer therapy is crucial, due to the increasing rates of many cancers throughout the world. For example, prostate cancer is one of the most prevalent cancers among U.S. males, with annual death rates currently estimated at over 40,000 (61). Current treatment for localized prostate cancer is limited to surgery or radiation therapy, whereas androgen ablation is generally accepted as the best method for treating metastatic prostate cancer. Unfortunately, a significant number of patients with advanced prostate cancer fail to demonstrate any initial positive response to androgen ablation therapy. Moreover, prostatic cells often lose their dependency on androgen during cancer progression, and androgen ablation becomes ineffective, leading to tumor progression and death within 3 years.
With the incidence of cancer and deaths resulting form cancer increasing, there remains a continuing need for the development of alternative therapeutic molecules and treatments for cancer. In particular, there is an on-going need for therapies that have minimal toxic side effects.